With modern advances in drug discovery and medicinal chemistry, the development of potent compounds in the present day is a fast paced and growing field. However, a major "make or break" point of many pharmaceutical entities between being successes in a laboratory to becoming clinically validated therapeutics that can make a difference in human health rests in what a small molecule or protein goes through once ingested and absorbed into the body, bloodstream, and periphery.
At this point, the major challenges that a drug molecule or biologic must face include:
Having the right physical properties for optimal ABSORPTION - how much is actually uptaken into circulation vs. into cells?
Having the proper localization to result in optimal DISTRIBUTION - where in the body does the drug entity localize?
Being able to survive METABOLISM by our body's natural elimination mechanisms - what happens as the host target begins to degrade the drug?
Controlling the rate of EXCRETION by our body's clearance mechanisms - how quickly is a drug eliminated from systemic circulation?
Minimizing off target TOXICITY - addressing a grand challenge of drug delivery requires elimination of off-target toxicity profiles.
*For a seminal review, please see Benedetti, et al.: "Drug metabolism and pharmacokinetics"
The Salgotra Lab uses several state-of-the-art instrumental techniques to gain quantitative and precise insight into drug metabolism dynamics and to study chemical and biological stability and compatibility of drug compounds, spanning mass spectrometry and HPLC based assays to using computer modeling to predict DMPK properties.
High Performance Liquid Chromatography (HPLC)
Liquid Chromatography - Mass Spectrometry
Immunohistochemistry (e.g. ELISA assays)
In Silico Approaches - Using Computer Models
Description: P-glycoprotein is a transporter protein which allows the influx and efflux of molecules across epithelium. Some orally administered drugs absorbed partially through this barrier due to efflux activity by P-glycoprotein and hence the required dose of the drug cannot reach the target site completely. For this project, we will study different flavonoid drugs which acts as P-glycoprotein inhibitor and can be given with these low bioavailable drugs to increase its bioavailability. This combination drug will help deliver the required dose of the drug at the target site. In our lab, we will focus on a variety of permeability assays, and plasma stability, plasma protein binding assays to study drug kinetics.
Description: As part of discovery process, the physiochemical and pharmacokinetic (ADME) properties of all molecules are evaluated utilizing in silico tools and further confirmed by running in vitro experiments in the lab. These experiments helps in understanding the absorption, distribution, metabolism and excretion aspects of these molecules. Our lab will focus on using in silico tools available online and setting up in vitro assays in lab to analyze the ADME aspects of small molecules. Future scientists in this lab will learn to write protocols, make dilutions, setting up and troubleshooting assays, using online research tools and reading research papers. Instrument handling and data analysis will be part of the project too.
Physiologic Based Pharmacokinetic (PBPK) Modeling Project to Simulate and Predict the Pharmacokinetics of Drugs
Understanding drug pharmacokinetics and predicting safe and effective dose is the most important aspect for all the drug molecules before it goes to humans. PBPK modeling is a computer modeling approach that incorporates blood flow and tissue composition of organs to define the pharmacokinetics of drugs. The software designed to do PBPK modeling include sources of physiochemical and biochemical variability and simulate the expected PK in a population of individuals.
This will be an online project and require students to collect the information from various research papers on the selected drug molecules and input that information into the software to simulate or predict the pharmacokinetics of drugs.